Cell division is the fundamental process by which all living things grow and reproduce. In unicellular organisms such as yeast and bacteria, each cell division doubles the number of organisms, while in multicellular species many rounds of cell division are required to produce a new tissue or organ and to replace cells lost by wear or by programmed cell death. Details of the cell division cycle may vary, but the basic process consists of three principle events. The first event, interphase, involves preparations for cell division, replication of the DNA and production of essential proteins. In the second event, mitosis, the nuclear material is divided and separates to opposite sides of the cell. The final event, cytokinesis, is division and fission of the cell cytoplasm. The sequence and timing of these cell cycle events is under the control of the cell cycle control system which regulates the process at various check points. Over the past two decades, much research has been devoted to studying the structure and functions of various proteins that regulate these events.
The entry and exit of a cell from mitosis is regulated by the synthesis and destruction of a family of activating proteins called cyclins. Cyclins act by binding to and activating a group of cyclin-dependent protein kinases (Cdks) which then phosphorylate and activate selected proteins involved in the mitotic process. Several types of cyclins exist. (Ciechanover, A. (1994) Cell 79:13-21.) Two principle types are mitotic cyclin, or cyclin B, which controls entry of the cell into mitosis, and G1 cyclin, which controls events that drive the cell out of mitosis.
The activation and targeting of specific Cdks is also under control of certain cell division cycle (CDC) regulator proteins. For example in humans, CDC37 is a protein kinase-targeting subunit that binds and stabilizes Cdk4 and permits it to complex with cyclin D1. The formation of this complex is an important step for entry into the cell cycle. (Stepanova, L. et al. (1996) Genes and Development 10:1491-1502.)
Guanine nucleotide-binding proteins (GTP-binding proteins or G-proteins) also participate in cell cycle control as well as in a wide range of other regulatory functions including metabolism, growth, differentiation, signal transduction, cytoskeletal organization, and intracellular vesicle transport and secretion. G-proteins control a diverse set of regulatory pathways in response to hormones, growth factors, neuromodulators, or other signaling molecules. When these molecules bind to transmembrane receptors, signals are propagated to effector molecules by intracellular signal transducing proteins.
Some G-proteins are heterotrimeric, composed of G.alpha., G.beta., and G .gamma. subunits. (Watson, S. and Arkinstall, S. (1994) The G-Protein Linked Receptor Facts Book, pp. 296-314.) In these proteins, G.alpha. binds to and hydrolyzes GTP resulting in the dissociation of G.alpha. from a tightly complexed G.beta..gamma. dimer. The released G.alpha. and G.beta..gamma. subunits in turn regulate the activity of effector proteins such as cGMP phosphodiesterase and adenyl cyclase. (Watson, J. A. et al. (1996) J. Biol. Chem. 271:28154-28160.) The low molecular weight (LMW) GTP-binding proteins are another class of G-proteins which consist of single polypeptides of 21-30 kDa. These proteins regulate cell growth, cell cycle control, protein secretion, and intracellular vesicle interaction. LMW GTP-binding proteins activate cellular proteins by transducing mitogenic signals in response to extracellular signals from receptors. (Tavitian, A. (1995) C. R. Seances Soc. Biol. Fil. 189:7-12.) During this process, the hydrolysis of GTP acts as an energy source as well as an on-off switch for the GTPase activity of the LMW GTP-binding proteins.
The LMW GTP-binding proteins have been grouped into four subfamilies: Ras, Rho, Rab and Ran. Specifically, Ras genes are essential in the control of cell proliferation and mutant Ras genes have been associated with cancer; Rho proteins control signal transduction in the process of linking receptors of growth factors to actin polymerization which is necessary for cell division; Rab proteins control the translocation of vesicles to and from membranes for protein localization, protein processing, and secretion; and Ran proteins are located in the cell nucleus and have a key role in nuclear protein import, control of DNA synthesis, and cell-cycle progression.
Cell cycle progression also requires co-ordinate expression of certain other proteins as well. N-glycosylation of proteins is required for progression through the G1 period of interphase. In yeast, for example, PSAL is an essential gene for G1 progression that encodes a protein with homology to NDP-hexose pyrophosphorylase; an enzyme that catalyzes the formation of activated sugar nucleotides. (Benton, B. K. et al. (1996) Curr. Genet. 29:106-113.) PSA1 appears to play a role in N-glycosylation and Gi progression perhaps by responding to levels of glycosylation necessary for G1 progression. Inhibitors of N-glycosylation, such as tunicamycin, induce G1 arrest in mammalian cells as well as yeast, suggesting that this mechanism is evolutionarily conserved in all eukaroytes. (Benton et al. supra.)
The discovery of new cell cycle related proteins and the polynucleotides encoding them satisfies a need in the art by providing new compositions which are useful in the diagnosis, treatment, and prevention of cancer and immune disorders.